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Discovery of CDH23 As a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

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Discovery of CDH23 As a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans RESEARCH ARTICLE Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans Bong Jik Kim1☯, Ah Reum Kim1☯, Chung Lee2,3, So Young Kim1, Nayoung K. D. Kim2, Mun Young Chang1, Jihye Rhee1, Mi-Hyun Park4, Soo Kyung Koo4, Min Young Kim5, Jin Hee Han5, Seung-ha Oh1, Woong-Yang Park2,6, Byung Yoon Choi5* 1 Department of Otorhinolaryngology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea, 2 Samsung Genome Institute, Samsung Medical Center, Seoul, Korea, a11111 3 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon, Korea, 4 Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Chungcheongbuk-do, Korea, 5 Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, Korea, 6 Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Korea ☯ These authors contributed equally to this work. * [email protected] OPEN ACCESS Citation: Kim BJ, Kim AR, Lee C, Kim SY, Kim NKD, Chang MY, et al. (2016) Discovery of CDH23 Abstract as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans. CDH23 mutations have mostly been associated with prelingual severe-to-profound sensori- PLoS ONE 11(10): e0165680. doi:10.1371/journal. neural hearing loss (SNHL) in either syndromic or nonsyndromic SNHL (DFNB12). Herein, pone.0165680 we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL Editor: David Meyre, McMaster University, (NS-SNHL). We screened 32 Korean adult probands with postlingual NS-SNHL sporadi- CANADA cally or in autosomal recessive fashion using targeted panel or whole exome sequencing. Received: August 14, 2016 We identified four (12.5%, 4/32) potential postlingual DFNB12 families that segregated the Accepted: October 14, 2016 recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Published: October 28, 2016 Three of the four families carried one definite pathogenic CDH23 variant previously known Copyright: © 2016 Kim et al. This is an open as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To access article distributed under the terms of the determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked Creative Commons Attribution License, which the minor allele frequency (MAF) of CDH23 variants detected from our postlingual NS- permits unrestricted use, distribution, and SNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromo- reproduction in any medium, provided the original author and source are credited. somes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%), confirm- Data Availability Statement: All relevant data are within the paper and its Supporting Information ing the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, files. Also, we have submitted the novel variants of MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher CDH23 that we detected by next generation than that from the prelingual NS-SNHL group. This study demonstrates an important contri- sequencing to the Leiden Open Variation Database (LOVD) (http://databases.lovd.nl/shared/genes/ bution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spec- CDH23) (submission numbers 0000081436 and trum of DFNB12 can be broadened even into the presbycusis, depending on the 0000081437). pathogenic potential of variants. We also propose that pathogenic potential of CDH23 vari- Funding: This work was supported by a grant of ants and the clinical fate of DFNB12 may be predicted by MAF. the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (www.mohw.go.kr/) (HI14C1867 and HI15C1632 PLOS ONE | DOI:10.1371/journal.pone.0165680 October 28, 2016 1 / 13 CDH23 and Progressive Postlingual Deafness in Koreans to BYC); and also by the Korea National Institute of Health intramural research grant 4861-307-210-13 Introduction (2012-NG61004-00 to SKK); and Korea Biobank Mutations of CDH23 (NM_022124) have been associated with type 1D Usher Syndrome Project (http://www.nih.go.kr/NIH_NEW/main.jsp) (USH1D) and nonsyndromic hearing loss (DFNB12), in a recessively transmitted manner [1, (4851-307, KBP-2014-035 to SKK). The funders had no role in study design, data collection and 2]. USH1D is associated with severe manifestations, including congenital profound deafness analysis, decision to publish, or preparation of the vestibular areflexia, and visual problems due to retinitis pigmentosa. Conversely, DFNB12, is manuscript. characterized by prelingual-onset nonsyndromic sensorineural hearing loss (SNHL) without Competing Interests: The authors have declared the impairment of vestibular or visual functions [3]. that no competing interests exist. The importance of CDH23 as a deafness gene has increasingly been recognized [4, 5]. In a Jap- anese study, CDH23 mutations were reported to be frequent after GJB2 and SLC26A4 in children and adults with hearing impairment [6]. Recently, CDH23 mutations have been reported in the Korean deaf population [7, 8], and genetic loads of CDH23 and its implications in the Korean pediatric population have also recently been reported [9]. Accordingly, p.P240L in CDH23 proved to exert a strong founder effect in the Korean pediatric population with severe-to-profound non- syndromic SNHL. Although CDH23 has been well established as a deafness gene, it is challenging to delineate its function by a functional assay due to its relatively large size with 69 exons and encoded cadherin 23, which includes a protein of 3,354 amino acids with 27 extracellular cadherin (EC) domains, a single transmembrane domain, and a short cytoplasmic domain [4, 5, 10]. CDH23 related hearing loss is known to be associated with its role in the tip links of the inner ear hair cells. Tip links are extracellular filaments that is proposed to act as a gate for the mechanotransduction channel. In other words, it transduces the mechanical forces that arise from the sound waves and head movement, allowing one to hear and maintain balance [11]. The interaction between protocadherin-15 (PCDH15) and CDH23—both localized in the upper and lower parts of the tip link complex—has been reported to form tip links [12]. Accordingly, both CDH23 and PCDH15 are necessary for normal mechanotransduction, and mutations in these genes have been associated with sensory impairment [10, 13]. CDH23 related hearing loss in USH1D and DFNB12 has mostly been associated with either congenital or prelingual-onset hearing loss [5]. However, some CDH23 mutations have been reported to be associated with postlingual-onset moderate hearing loss in humans [6, 14]. Fur- thermore, some Cdh23 mutant alleles in mice manifested age-related hearing loss, which started as high-frequency hearing loss that eventually progressed to profound impairment with varying degrees of rapidity, as explained by the allelism and modifier gene [15–17]. Moreover, Cdh23 was also found to be susceptible to noise induced hearing loss, which is a different type of SNHL [18, 19]. However, the contribution of CDH23 to the human postlingual-onset hear- ing loss has not been adequately investigated. Moreover, mechanisms responsible for different phenotypes of CDH23 mutations have not been fully elucidated to date. Herein, we adopted a genetic epidemiologic approach to objectively illustrate the impor- tance of CDH23 in postlingual-onset SNHL and to investigate the causal relationship between genotypes and phenotypes. In brief, we estimated the carrier frequency of CDH23 mutations in postlingual adult-onset inherited hearing loss, which were segregated in either a sporadic or autosomal recessive (AR) fashion based on the ethnic-specific minor allele frequency (MAF) filtering process to investigate the contribution of CDH23 and further tried to delineate the genotypic hierarchy of CDH23 mutations that determine the fate of DFNB12. Material and Methods Ethical considerations This study was approved by the Institutional Review Boards of Seoul National University Hos- pital (IRBY-H-0905-041-281) and Seoul National University Bundang Hospital (IRB-B-1007- PLOS ONE | DOI:10.1371/journal.pone.0165680 October 28, 2016 2 / 13 CDH23 and Progressive Postlingual Deafness in Koreans 105-402). Written informed consent was obtained from all study participants. In the case of minors, written informed consent was obtained from parents or guardians. Study participants and clinical data Patients with postlingual adult-onset SNHL, segregated in either a sporadic or AR fashion, were selected from our Korean cohorts, and published data from a previous study on pediatric cohorts were retrieved for analysis [9]. Additionally, our adult cohort fulfilled the following cri- teria: 1) bilateral nonsyndromic hearing loss, 2) moderate hearing loss with progressive nature, and 3) onset of hearing loss at the age of 15 or older, excluding the possibility of later develop- ment of USH1D. Also, when possible, family members were invited to participate in the study. Clinical data were obtained for this study population, including gender, age, medical history, physical examination, and audiological test results. The hearing threshold was calculated by averaging
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